Cardiovascular Thrombotic Events

Nonsteroidal
anti-inflammatory drugs (NSAIDs) cause an increased risk of serious
cardiovascular thrombotic events, including myocardial infarction and stroke,
which can be fatal. This risk may occur early in treatment and may increase
with duration of use. (see WARNINGS.)

Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs cause an increased
risk of serious gastrointestinal (GI) adverse events including bleeding,
ulceration, and perforation of the stomach or intestines, which can be fatal.
These events can occur at any time during use and without warning symptoms.
Elderly patients and patients with a prior history of peptic ulcer disease
and/or GI bleeding are at greater risk for serious GI events. (see WARNINGS.)

DESCRIPTION

CATAFLAM® (diclofenac potassium immediate-release
tablets) is a benzeneacetic acid derivative. CATAFLAM is available as
immediate-release tablets of 50 mg (light brown) for oral administration.
Diclofenac potassium is a white or slightly yellowish crystalline powder and is
sparingly soluble in water at 25°C. The chemical name is
2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monopotassium salt. The
molecular weight is 334.25. Its molecular formula is C14H10Cl2NKO2, and it has
the following structural formula

INDICATIONS

Carefully consider the potential benefits and risks of
CATAFLAM® (diclofenac potassium immediate-release tablets) and other treatment
options before deciding to use CATAFLAM. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (seeWARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of
CATAFLAM® (diclofenac potassium immediate-release tablets) and other treatment
options before deciding to use CATAFLAM. Use the lowest effective dose for the
shortest duration consistent with individual patient treatment goals (see WARNINGS;
Gastrointestinal Bleeding, Ulceration, and Perforation).

After observing the response to initial therapy with
CATAFLAM, the dose and frequency should be adjusted to suit an individual
patient's needs.

For treatment of pain or primary dysmenorrhea the
recommended dosage is 50 mg three times a day. With experience, physicians may
find that in some patients an initial dose of 100 mg of CATAFLAM, followed by
50-mg doses, will provide better relief.

For the relief of osteoarthritis the recommended dosage
is 100-150 mg/day in divided doses, 50 mg twice a day. or three times a day.

For the relief of rheumatoid arthritis the recommended
dosage is 150-200 mg/day in divided doses, 50 mg three times a day or four
times a day.

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

DRUG INTERACTIONS

See Table 2 for clinically significant drug interactions
with diclofenac.

Table 2: Clinically Significant Drug Interactions with
Diclofenac

Drugs That Interfere with Hemostasis

Clinical Impact:

Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.

Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

Intervention:

Concomitant use of CATAFLAM and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematological Toxicity). CATAFLAM is not a substitute for low dose aspirin for cardiovascular protection.

In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.

Intervention:

During concomitant use of CATAFLAM and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.

During concomitant use of CATAFLAM and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).

When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics

Clinical Impact:

Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of CATAFLAM with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia)

Digoxin

Clinical Impact:

The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

Intervention:

During concomitant use of CATAFLAM and digoxin, monitor serum digoxin levels.

Lithium

Clinical Impact:

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.

Intervention:

During concomitant use of CATAFLAM and lithium, monitor patients for signs of lithium toxicity.

Methotrexate

Clinical Impact:

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

Intervention:

During concomitant use of CATAFLAM and methotrexate, monitor patients for methotrexate toxicity.

Cyclosporine

Clinical Impact:

Concomitant use of CATAFLAM and cyclosporine may increase cyclosporine’s’ nephrotoxicity.

Intervention:

During concomitant use of CATAFLAM and cyclosporine, monitor patients for signs of worsening renal function.

NSAIDs and Salicylates

Clinical Impact:

Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation).

Intervention:

The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.

Pemetrexed

Clinical Impact:

Concomitant use of CATAFLAM and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).

Intervention:

During concomitant use of CATAFLAM and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

CYP2C9 Inhibitors or Inducers:

Clinical Impact:

Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas coadministration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.

Intervention:

A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY; Pharmacokinetics).

Warnings

WARNINGS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and
nonselective NSAIDs of up to three years duration have shown an increased risk
of serious cardiovascular (CV) thrombotic events, including myocardial
infarction (MI) and stroke, which can be fatal. Based on available data, it is
unclear that the risk for CV thrombotic events is similar for all NSAIDs. The
relative increase in serious CV thrombotic events over baseline conferred by
NSAID use appears to be similar in those with and without known CV disease or
risk factors for CV disease. However, patients with known CV disease or risk
factors had a higher absolute incidence of excess serious CV thrombotic events,
due to their increased baseline rate. Some observational studies found that
this increased risk of serious CV thrombotic events began as early as the first
weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.

To minimize the potential risk for an adverse CV event in
NSAID-treated patients, use the lowest effective dose for the shortest duration
possible. Physicians and patients should remain alert for the development of
such events, throughout the entire treatment course, even in the absence of
previous CV symptoms. Patients should be informed about the symptoms of serious
CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of
aspirin mitigates the increased risk of serious CV thrombotic events associated
with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac,
increases the risk of serious gastrointestinal (GI) events (see WARNINGS;
Gastrointestinal Bleeding, Ulceration, and Perforation).

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled, clinical trials of a COX-2
selective NSAID for the treatment of pain in the first 10-14 days following
CABG surgery found an increased incidence of myocardial infarction and stroke.
NSAIDs are contraindicated in the setting of CABG (seeCONTRAINDICATIONS).

Post-MI Patients

Observational studies conducted in the Danish National
Registry have demonstrated that patients treated with NSAIDs in the post-MI
period were at increased risk of reinfarction, CV-related death, and all-cause
mortality beginning in the first week of treatment. In this same cohort, the
incidence of death in the first year post-MI was 20 per 100 person years in
NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed
patients. Although the absolute rate of death declined somewhat after the first
year post-MI, the increased relative risk of death in NSAID users persisted
over at least the next four years of follow-up.

Avoid the use of CATAFLAM in patients with a recent MI
unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If CATAFLAM is used in patients with a recent MI, monitor
patients for signs of cardiac ischemia.

Gastrointestinal Bleeding, Ulceration, And Perforation

NSAIDs, including diclofenac, cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the esophagus, stomach, small intestine, or
large intestine, which can be fatal. These serious adverse events can occur at
any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients, who develop a serious upper GI adverse event on
NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding or perforation
caused by NSAIDs occurred in approximately 1% of patients treated for 3-6
months, and in about 2%-4% of patients treated for one year. However, even
short-term therapy is not without risk.

Risk Factors For GI Bleeding, Ulceration, And Perforation

Patients with a prior history of peptic ulcer disease
and/or GI bleeding who use NSAIDs had a greater than 10-fold increased risk for
developing a GI bleed compared to patients without these risk factors. Other
factors that increase the risk of GI bleeding in patients treated with NSAIDs
include longer duration of NSAID therapy, concomitant use of oral
corticosteroids, aspirin, anticoagulants, or selective serotoninreuptake
inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health
status. Most postmarketing reports of fatal GI events occurred in elderly or
debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.

Strategies to Minimize the GI Risks in NSAID-treated
patients:

Use the lowest effective dosage for the shortest possible
duration.

Avoid administration of more than one NSAID at a time

Avoid use in patients at higher risk unless benefits are
expected to outweigh the increased risk of bleeding. For such patients, as well
as those with active GI bleeding, consider alternate therapies other than
NSAIDs.

Remain alert for signs and symptoms of GI ulceration and
bleeding during NSAID therapy.

If a serious GI adverse event is suspected, promptly
initiate evaluation and treatment, and discontinue CATAFLAM until a serious GI
adverse event is ruled out.

In the setting of concomitant use of low-dose aspirin for
cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see
PRECAUTIONS; DRUG INTERACTIONS).

Hepatotoxicity

In clinical trials of diclofenac- containing products,
meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were
observed in about 2% of approximately 5,700 patients at some time during
diclofenac treatment (ALT was not measured in all studies).

In a large, open-label, controlled trial of 3,700
patients treated with oral diclofenac sodium for 2-6 months, patients were
monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks.
Meaningful elevations of ALT and/or AST occurred in about 4% of patients and
included marked elevations (greater than 8 times the ULN) in about 1% of the
3,700 patients. In that open-label study, a higher incidence of borderline
(less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater
than 8 times the ULN) elevations of ALT or AST was observed in patients
receiving diclofenac when compared to other NSAIDs. Elevations in transaminases
were seen more frequently in patients with osteoarthritis than in those with
rheumatoid arthritis.

Almost all meaningful elevations in transaminases were
detected before patients became symptomatic. Abnormal tests occurred during the
first 2 months of therapy with diclofenac in 42 of the 51 patients in all
trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced
hepatotoxicity have been reported in the first month, and in some cases, the
first 2 months of therapy, but can occur at any time during treatment with
diclofenac. Postmarketing surveillance has reported cases of severe hepatic
reactions, including liver necrosis, jaundice, fulminant hepatitis with and
without jaundice, and liver failure. Some of these reported cases resulted in
fatalities or liver transplantation.

In a European retrospective population-based,
case-controlled study, 10 cases of diclofenac associated drug-induced liver
injury with current use compared with non-use of diclofenac were associated
with a statistically significant 4-fold adjusted odds ratio of liver injury. In
this particular study, based on an overall number of 10 cases of liver injury
associated with diclofenac, the adjusted odds ratio increased further with
female gender, doses of 150 mg or more, and duration of use for more than 90
days.

Physicians should measure transaminases at baseline and
periodically in patients receiving long-term therapy with diclofenac, because
severe hepatotoxicity may develop without a prodrome of distinguishing
symptoms. The optimum times for making the first and subsequent transaminase
measurements are not known. Based on clinical trial data and postmarketing experiences,
transaminases should be monitored within 4 to 8 weeks after initiating
treatment with diclofenac. However, severe hepatic reactions can occur at any
time during treatment with diclofenac.

To minimize the potential risk for an adverse liver
related event in patients treated with CATAFLAM, use the lowest effective dose
for the shortest duration possible. Exercise caution when prescribing CATAFLAM
with concomitant drugs that are known to be potentially hepatotoxic (e.g.,
acetaminophen, antibiotics, anti-epileptics).

Hypertension

NSAIDs, including CATAFLAM can lead to new onset of
hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking angiotensin
converting enzyme (ACE) inhibitors, thiazides diuretics or loop diuretics may
have impaired response to these therapies when taking NSAIDs (see
PRECAUTIONS; DRUG INTERACTIONS).

Monitor blood pressure (BP) during the initiation of
NSAID treatment and throughout the course of therapy.

Heart Failure And Edema

The Coxib and traditional NSAID Trialists' Collaboration
meta-analysis of randomized controlled trials demonstrated an approximately
two-fold increase in hospitalization for heart failure in COX-2
selective-treated patients and nonselective NSAID-treated patients compared to
placebo-treated patients. In a Danish National Registry study of patients with
heart failure, NSAID use increased the risk of MI, hospitalization for heart
failure, and death.

Additionally, fluid retention and edema have been
observed in some patients treated with NSAIDs. Use of diclofenac may blunt the
CV effects of several therapeutic agents used to treat these medical conditions
(e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) (see
PRECAUTIONS; DRUG INTERACTIONS).

Avoid the use of CATAFLAM in patients with severe heart
failure unless the benefits are expected to outweigh the risk of worsening
heart failure. If CATAFLAM is used in patients with severe heart failure,
monitor patients for signs of worsening heart failure.

Renal Toxicity And Hyperkalemia

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom
renal prostaglandins have a compensatory role in the maintenance of renal
perfusion. In these patients, administration of an NSAID may cause a
dose-dependent reduction in prostaglandin formation and, secondarily, in renal
blood flow, which may precipitate overt renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal function,
dehydration, hypovolemia, heart failure, liver dysfunction, those taking
diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID
therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical
studies regarding the use of CATAFLAM in patients with advanced renal disease.
The renal effects of CATAFLAM may hasten the progression of renal dysfunction
in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic
patients prior to initiating CATAFLAM. Monitor renal function in patients with
renal or hepatic impairment, heart failure, dehydration, or hypovolemia during
use of CATAFLAM (see PRECAUTIONS; DRUG INTERACTIONS). Avoid the
use of CATAFLAM in patients with advanced renal disease unless the benefits are
expected to outweigh the risk of worsening renal function. If CATAFLAM is used
in patients with advanced renal disease, monitor patients for signs of
worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including
hyperkalemia, have been reported with use of NSAIDs, even in some patients
without renal impairment. In patients with normal renal function, these effects
have been attributed to a hyporeninemic-hypoaldosteronism state.

Anaphylactic Reactions

Diclofenac has been associated with anaphylactic
reactions in patients with and without known hypersensitivity to diclofenac and
in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS, WARNINGS;
Exacerbation of Asthma Related to Aspirin Sensitivity).

Exacerbation Of Asthma Related To Aspirin Sensitivity

A subpopulation of patients with asthma may have
aspirin-sensitive asthma which may include chronic rhinosinusitis complicated
by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to
aspirin and other NSAIDs. Because cross-reactivity between aspirin and other
NSAIDs has been reported in such aspirin-sensitive patients, CATAFLAM is
contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS).
When CATAFLAM is used in patients with preexisting asthma (without known
aspirin sensitivity), monitor patients for changes in the signs and symptoms of
asthma.

Serious Skin Reactions

NSAIDs, including diclofenac, can cause serious skin
adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS),
and toxic epidermal necrolysis (TEN), which can be fatal. These serious events
may occur without warning. Inform patients about the signs and symptoms of
serious skin reactions and discontinue the use of CATAFLAM at the first
appearance of skin rash or any other sign of hypersensitivity. CATAFLAM is
contraindicated in patients with previous serious skin reactions to NSAIDs (see
CONTRAINDICATIONS).

Premature Closure Of Fetal Ductus Arteriosus

Diclofenac may cause premature closure of the fetal
ductus arteriosus Avoid use of NSAIDs, including CATAFLAM, in pregnant women
starting at 30 weeks of gestation (third trimester) (see PRECAUTIONS; Pregnancy).

Hematological Toxicity

Anemia has occurred in NSAID-treated patients. This may be
due to occult or gross blood loss, fluid retention, or an incompletely
described effect upon erythropoiesis. If a patient treated with CATAFLAM has
any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including CATAFLAM, may increase the risk of
bleeding events. Co-morbid conditions such as coagulation disorders,
concomitant use of warfarin and other anticoagulants, antiplatelet agents
(e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor
these patients for signs of bleeding (see PRECAUTIONS; DRUG
INTERACTIONS).

Precautions

PRECAUTIONS

General

CATAFLAM® (diclofenac potassium immediate-release
tablets) cannot be expected to substitute for corticosteroids or to treat
corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead
to disease exacerbation. Patients on prolonged corticosteroid therapy should
have their therapy tapered slowly if a decision is made to discontinue
corticosteroids and the patient should be observed closely for any evidence of
adverse effects, including adrenal insufficiency and exacerbation of symptoms
of arthritis.

The pharmacological activity of CATAFLAM in reducing
fever and inflammation may diminish the utility of these diagnostic signs in
detecting complications of presumed noninfectious, painful conditions.

Information For Patients

Advise the patient to read the FDA-approved patient
labeling (Medication Guide) that accompanies each prescription dispensed.
Inform patients, families, or their caregivers of the following information
before initiating therapy with CATAFLAM and periodically during the course of
ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of
cardiovascular thrombotic events, including chest pain, shortness of breath,
weakness, or slurring of speech, and to report any of these symptoms to their
healthcare provider immediately (see WARNINGS; Cardiovascular
Thrombotic Events).

Gastrointestinal Bleeding, Ulceration, And Perforation

Advise patients to report symptoms of ulcerations and
bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to
their health care provider. In the setting of concomitant use of low-dose
aspirin for cardiac prophylaxis, inform patients of the increased risk for the
signs and symptoms of GI bleeding (see WARNINGS; Gastrointestinal
Bleeding, Ulceration, and Perforation).

Heart Failure And Edema

Advise patients to be alert for the symptoms of
congestive heart failure including shortness of breath, unexplained weight
gain, or edema and to contact their healthcare provider if such symptoms occur (see
WARNINGS; Heart Failure and Edema).

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction
(eg, difficulty breathing, swelling of the face or throat). Instruct patients
to seek immediate emergency help if these occur (see WARNINGS; Anaphylactic
Reactions).

Serious Skin Reactions

Advise patients to stop CATAFLAM immediately if they
develop any type of rash and contact their healthcare provider as soon as
possible (see WARNINGS; Serious Skin Reactions).

Female Fertility

Advise females of reproductive potential who desire
pregnancy that NSAIDs, including VOLTAREN, may be associated with a reversible
delay in ovulation (see PRECAUTIONS; Carcinogenesis, Mutagenesis,
Impairment of Fertility).

Fetal Toxicity

Inform pregnant women to avoid use of CATAFLAM and other
NSAIDs, starting at 30 weeks gestation because of the risk of the premature
closure of the fetal ductus arteriosus (see WARNINGS; Premature
Closure of Fetal Ductus Arteriosus).

Avoid Concomitant Use Of NSAIDs

Inform patients that the concomitant use of CATAFLAM with
other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended
due to the increased risk of gastrointestinal toxicity, and little or no
increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration,
and Perforation and Drug Interactions). Alert patients that NSAIDs may
be present in “over the counter” medications for treatment of colds, fever, or
insomnia.

Use Of NSAIDS And Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly
with CATAFLAM until they talk to their healthcare provider (see PRECAUTIONS;
DRUG INTERACTIONS).

Masking Of Inflammation And Fever

The pharmacological activity of CATAFLAM in reducing
fever and inflammation, and possibly fever, may diminish the utility of these
diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal
injury can occur without warning symptoms or signs, consider monitoring
patients on long-term NSAID treatment with a CBC and a chemistry profile
periodically (see WARNINGS; Gastrointestinal Bleeding, Ulceration
and Perforation, and Hepatotoxicity).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term carcinogenicity
studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.1
times the maximum recommended human dose (MRHD) of CATAFLAM, 200 mg/day, based
on body surface area (BSA) comparison) have revealed no significant increase in
tumor incidence. A 2-year carcinogenicity study conducted in mice employing
diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.007 times the
MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.02
times the MRHD based on BSA comparison) in females did not reveal any oncogenic
potential.

Mutagenesis

Diclofenac sodium did not show
mutagenic activity in in vitropoint mutation assays in mammalian (mouse
lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in
several mammalian in vitro and in vivo tests, including dominantlethal and
male germinal epithelial chromosomal studies in mice, and nucleusanomaly and
chromosomal aberration studies in Chinese hamsters.

Impairment Of Fertility

Diclofenac sodium administered
to male and female rats at 4 mg/kg/day (approximately 0.2 times the MRHD based
on BSA comparison) did not affect fertility.

Based on the mechanism of
action, the use of prostaglandin-mediated NSAIDs, including CATAFLAM, may delay
or prevent rupture of ovarian follicles, which has been associated with
reversible infertility in some women. Published animal studies have shown that
administration of prostaglandin synthesis inhibitors has the potential to
disrupt prostaglandin-mediated follicular rupture required for ovulation. Small
studies in women treated with NSAIDs have also shown a reversible delay in
ovulation. Consider withdrawal of NSAIDs, including CATAFLAM, in women who have
difficulties conceiving or who are undergoing investigation of infertility.

Pregnancy

Risk Summary

Use of NSAIDs, including
CATAFLAM, during the third trimester of pregnancy increases the risk of
premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs,
including CATAFLAM, in pregnant women starting at 30 weeks of gestation (third
trimester) (see WARNINGS; Premature Closure of Fetal Ductus Arterious).

There are no adequate and
well-controlled studies of CATAFLAM in pregnant women. Data from observational
studies regarding potential embryofetal risks of NSAID use in women in the
first or second trimesters of pregnancy are inconclusive. In the general U.S.
population, all clinically recognized pregnancies, regardless of drug exposure,
have a background rate of 2-4% for major malformations, and 15-20% for
pregnancy loss. In animal reproduction studies, no evidence of teratogenicity
was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis
at doses up to approximately 0.5, 0.5, and 1 times, respectively, the
maximum recommended human dose (MRHD) of CATAFLAM, despite the presence of
maternal and fetal toxicity at these doses [see Data]. Based on animal
data, prostaglandins have been shown to have an important role in endometrial
vascular permeability, blastocystimplantation, and decidualization. In animal
studies, administration of prostaglandin synthesis inhibitors such as
diclofenac, resulted in increased pre- and post-implantation loss.

Data

Animal Data

Reproductive and developmental studies in animals
demonstrated that diclofenac sodium administration during organogenesis did not
produce teratogenicity despite the induction of maternal toxicity and fetal
toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.5 times the
maximum recommended human dose [MRHD] of CATAFLAM, 200 mg/day, based on body
surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10
mg/kg/day (approximately 0.5 and 1 times, respectively, the MRHD based on BSA
comparison). In a study in which pregnant rats were orally administered 2 or 4
mg/kg diclofenac (0.1 and 0.2 times the MRHD based on BSA) from Gestation Day
15 through Lactation Day 21, significant maternal toxicity (peritonitis,
mortality) was noted. These maternally toxic doses were associated with
dystocia, prolonged gestation, reduced fetal weights and growth, and reduced
fetal survival. Diclofenac has been shown to cross the placental barrier in
mice, rats, and humans.

Labor Or Delivery

There are no studies on the effects of CATAFLAM during
labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit
prostaglandin synthesis, cause delayed parturition, and increase the incidence
of stillbirth.

Nursing Mothers

Risk Summary

Based on available data, diclofenac may be present in
human milk. The developmental and health benefits of breastfeeding should be
considered along with the mother's clinical need for CATAFLAM and any potential
adverse effects on the breastfed infant from the CATAFLAM or from the
underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150
mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose
of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12
women using diclofenac (after either 100 mg/day orally for 7 days or a single
50 mg intramuscular dose administered in the immediate postpartum period).

Pediatric Use

Safety and effectiveness in pediatric patients have not
been established.

Diclofenac is known to be substantially excreted by the
kidney, and the risk of adverse reactions to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and
it may be useful to monitor renal function (See CLINICAL PHARMACOLOGY, ADVERSE
REACTIONS).

Manage patients with symptomatic and supportive care
following an NSAID overdosage. There are no specific antidotes. Consider emesis
and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of
body weight in pediatric patients) and/or osmotic cathartic in symptomatic
patients seen within four hours of ingestion in patients with a large overdose
(5 to 10 times the recommended dosage). Forced diuresis, alkalinization of
urine, hemodialysis, or hemoperfusion may not be useful due to high protein
binding.

For additional information about overdosage treatment
contact a poison control center (1-800-2221222).

History of asthma, urticaria, or allergic-type reactions
after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic
reactions to NSAIDs have been reported in such patients (seeWARNINGS; Anaphylactic
Reactions, Exacerbation of Asthma Related to Aspirin Sensitivity).

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of action of
CATAFLAM, like that of other NSAIDs, is not completely understood but involves
inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent
inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrations
reached during therapy have produced in vivo effects. Prostaglandins sensitize
afferent nerves and potentiate the action of bradykinin in inducing pain in
animal models. Prostaglandins are mediators of inflammation. Because diclofenac
is an inhibitor of prostaglandin synthesis, its mode of action may be due to a
decrease of prostaglandins in peripheral tissues.

Pharmacokinetics

Absorption

Diclofenac is 100% absorbed
after oral administration compared to IV administration as measured by urine
recovery. However, due to first-pass metabolism, only about 50% of the absorbed
dose is systemically available (see Table 1). In some fasting volunteers,
measurable plasma levels are observed within 10 minutes of dosing with
CATAFLAM. Peak plasma levels are achieved approximately 1 hour in fasting
normal volunteers, with a range of .33 to 2 hours. Food has no significant
effect on the extent of diclofenac absorption. However, there is usually a
delay in the onset of absorption and a reduction in peak plasma levels of
approximately 30%.

Table 1: Pharmacokinetic Parameters for Diclofenac

PK Parameter

Normal Healthy Adults (20-52 years)

Mean

Coefficient of Variation (%)

Absolute Bioavailability (%) [N = 7]

55

40

Tmax (hr) [N = 65]

1.0

76

Oral Clearance (CL/F; mL/min) [N = 61]

622

21

Renal Clearance (% unchanged drug in urine) [N = 7]

< 1

—

Apparent Volume of Distribution (V/F; L/kg) [N = 61]

1.3

33

Terminal Half-life (hr) [N = 48]

1.9

29

Distribution

The apparent volume of
distribution (V/F) of diclofenac potassium is 1.3 L/kg.

Diclofenac is more than 99%
bound to human serum proteins, primarily to albumin. Serum protein binding is
constant over the concentration range (0.15-105 mcg/mL) achieved with
recommended doses.

Diclofenac diffuses into and
out of the synovial fluid. Diffusion into the joint occurs when plasma levels
are higher than those in the synovial fluid, after which the process reverses
and synovial fluid levels are higher than plasma levels. It is not known
whether diffusion into the joint plays a role in the effectiveness of
diclofenac.

Elimination

Metabolism

Five diclofenac metabolites
have been identified in human plasma and urine. The metabolites include
4'hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and
3'-hydroxy-4'-methoxy-diclofenac. The major diclofenac metabolite,
4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of
4'-hydroxy-diclofenac is primarily mediated by CYP2C9. Both diclofenac and its
oxidative metabolites undergo glucuronidation or sulfation followed by biliary
excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by
CYP2C8may also play a role in diclofenac metabolism. CYP3A4 is responsible for
the formation of minor metabolites, 5-hydroxy- and 3'-hydroxy-diclofenac. In
patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy-
and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound
after single oral dosing compared to 27% and 1% in normal healthy subjects.

Excretion

Diclofenac is eliminated through metabolism and
subsequent urinary and biliary excretion of the glucuronide and the sulfate
conjugates of the metabolites. Little or no free unchanged diclofenac is
excreted in the urine. Approximately 65% of the dose is excreted in the urine
and approximately 35% in the bile as conjugates of unchanged diclofenac plus
metabolites. Because renal elimination is not a significant pathway of
elimination for unchanged diclofenac, dosing adjustment in patients with mild
to moderate renal dysfunction is not necessary. The terminal half-life of
unchanged diclofenac is approximately 2 hours.

Special Populations

Pediatric: The pharmacokinetics of CATAFLAM has
not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race have
not been identified.

Hepatic Impairment: Hepatic metabolism accounts
for almost 100% of CATAFLAM elimination, so patients with hepatic disease may
require reduced doses of CATAFLAM compared to patients with normal hepatic
function.

Renal Impairment: Diclofenac pharmacokinetics has
been investigated in subjects with renal insufficiency. No differences in the
pharmacokinetics of diclofenac have been detected in studies of patients with
renal impairment. In patients with renal impairment (inulin clearance 60-90,
30-60, and < 30 mL/min; N=6 in each group), AUC values and elimination rate
were comparable to those in healthy subjects.

Drug Interactions Studies

Voriconazole: When co-administered with
voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the Cmax and AUC of
diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS; DRUG
INTERACTIONS).

Aspirin: When NSAIDs were administered with
aspirin, the protein binding of NSAIDs were reduced, although the clearance of
free NSAID was not altered. The clinical significance of this interaction is
not known. See Table 2 for clinically significant drug interactions of NSAIDs
with aspirin (see PRECAUTIONS; DRUG INTERACTIONS).

Medication Guide

PATIENT INFORMATION

Medication Guide for Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs)

What is the most important information I should know
about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAIDs can cause serious side effects, including:

Increased risk of a heart attack or stroke that can
lead to death. This risk may happen early in treatment and may increase:

with increasing doses of NSAIDs

with longer use of NSAIDs

Do not take NSAIDs right before or after a heart
surgery called a “coronary artery bypass graft (CABG).” Avoid taking NSAIDs
after a recent heart attack, unless your healthcare provider tells you to. You
may have an increased risk of another heart attack if you take NSAIDs after a
recent heart attack.

Increased risk of bleeding, ulcers, and tears
(perforation) of the esophagus (tube leading from the mouth to the stomach),
stomach and intestines:

any time during use

without warning symptoms

that may cause death

The risk of getting an ulcer or bleeding increases
with:

past history of stomach ulcers, or stomach or intestinal
bleeding with use of NSAIDs

are pregnant or plan to become pregnant. Talk to your
healthcare provider if you are considering taking NSAIDs during pregnancy. You
should not take NSAIDs after 29 weeks of pregnancy.

are breastfeeding or plan to breastfeed.

Tell your healthcare provider about all of the
medicines you take, including prescription or over-the-counter medicines,
vitamins or herbal supplements. NSAIDs and some other medicines can
interact with each other and cause serious side effects. Do not start taking
any new medicine without talking to your healthcare provider first.

What are the possible side effects of NSAIDs?

NSAIDs can cause serious side effects, including:

See “What is the most important information I should
know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?

there is blood in your bowel movement or it is black and
sticky like tar

your skin or eyes look yellow

indigestion or stomach pain

flu-like symptoms

unusual weight gain

skin rash or blisters with fever

swelling of the arms and legs, hands and feet

If you take too much of your NSAID, call your
healthcare provider or get medical help right away.

These are not all the possible side effects of NSAIDs.
For more information, ask your healthcare provider or pharmacist about NSAIDs.

Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088

Other information about NSAIDs

Aspirin is an NSAID medicine but it does not increase the
chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and
intestines. Aspirin can also cause ulcers in the stomach and intestines.

Some NSAIDs are sold in lower doses without a
prescription (over-the-counter). Talk to your healthcare provider before using
over-the-counter NSAIDs for more than 10 days.

General information about the safe and effective use
of NSAIDs

Medicines are sometimes prescribed for purposes other
than those listed in a Medication Guide. Do not use NSAIDs for a condition for
which it was not prescribed. Do not give NSAIDs to other people, even if they
have the same symptoms that you have. It may harm them.

If you would like more information about NSAIDs, talk
with your healthcare provider. You can ask your pharmacist or healthcare
provider for information about NSAIDs that is written for health professionals.